The protozoan parasite Toxoplasma gondii infects all nucleated cells and establishes life-long chronic infections in virtually any warm-blooded vertebrate. Eliminating the ability of this parasite to establish chronic infections in humans and animals is central to controlling its pathogenesis, however, there is currently no human vaccine or drug capable of doing this. Our lab has identified a large superfamily of >182 SRS protein adhesins that are essential for 1) entry into host cells and 2) regulating host immunity in order to establish chronic infections. The SRS proteins are regulated in a development-specific manner, and we showed by gene-knockout studies that four of these antigens expressed by the tachyzoite stage are critical virulence factors: SAG1, SAG2, SRS2 and SAG3. SAG3 is a pivotal adhesin required for establishing infection, whereas SAG1, SAG2 and SRS2 are primarily immunomodulating factors that elicit strong immunity in all infected hosts. We recently produced parasite strains deficient in the expression of SAG1, SAG2, or both SAG1 and SAG2. Individual knock-out lines were only slightly attenuated in murine infections, however, the double knock-out was significantly less virulent, by a factor of at least 2 logs. The surface antigens SRS1 and SRS2 were greatly upregulated in their expression in the doubly deficient SAG1 and SAG2 knockout parasites. Previously, we identified that the majority of mouse virulent Toxoplasma strains poorly express SRS2, whereas all avirulent strains are high expressors. We tested whether SRS2 expression level was sufficient to alter the mouse virulence phenotype. When expressed transgenically in a virulent strain at levels equivalent to those found in avirulent strains, the SRS2 transgenic strains were highly attenuated. These data suggest that SRS2 is a pivotal virulence factor and that expression level is a critical determinant governing the outcome of infection. We are currently investigating the molecular and cellular basis of SRS2 mediated alterations in Toxoplasma pathogenesis in the murine infection model. Understanding the structural basis and cellular receptors for host cell entry within this superfamily of SRS antigens, and the type of immunity induced during natural infections should lay the foundation for therapeutic interventions, either prophylactic or vaccine-based, to limit infectivity and induce sterilizing immunity against this widespread zoonotic pathogen.